EP1651626A1 - Derives d'uree et leur utilisation comme inhibiteurs des tyrosine kinases - Google Patents

Derives d'uree et leur utilisation comme inhibiteurs des tyrosine kinases

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Publication number
EP1651626A1
EP1651626A1 EP04763077A EP04763077A EP1651626A1 EP 1651626 A1 EP1651626 A1 EP 1651626A1 EP 04763077 A EP04763077 A EP 04763077A EP 04763077 A EP04763077 A EP 04763077A EP 1651626 A1 EP1651626 A1 EP 1651626A1
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EP
European Patent Office
Prior art keywords
phenyl
urea
yloxy
fluoro
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04763077A
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German (de)
English (en)
Inventor
Günter Hölzemann
Karl-August Ackermann
Wolfgang Stähle
Alfred Jonczyk
Wilfried Rautenberg
Francesc Mitjans
Elisabet Rosell-Vives
Jaume Adan
Marta Soler
Helene Crassier
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Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1651626A1 publication Critical patent/EP1651626A1/fr
Withdrawn legal-status Critical Current

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the present invention relates to compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or Raf kinases, plays a role, furthermore pharmaceutical compositions which contain these compounds and the use of the compounds for treatment of kinase-related diseases.
  • the present invention relates to compounds that inhibit, regulate and / or modulate the signal transduction of tyrosine kinases, compositions containing these compounds, and methods for their use in the treatment of tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor growth, arteriosclerosis , age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.
  • tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor growth, arteriosclerosis , age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.
  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues on protein substrates. It is believed that tyrosine kinases play an essential role in signal transduction in various cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, the tyrosine kinases have been shown to be important factors cell proliferation, carcinogenesis and cell differentiation.
  • the tyrosine kinases can be divided into receptor tyrosine kinases and cytosolic tyrosine kinases.
  • the receptor tyrosine kinases have an extracellular part, a transmembrane part and an intracellular part, while the cytosolic tyrosine kinases are only present intracellularly.
  • the receptor tyrosine kinases consist of a large number of transmembrane receptors with different biological effectiveness. About 20 different subfamilies of receptor tyrosine kinases have been identified.
  • a tyrosine kinase subfamily called the HER subfamily consists of EGFR, HER2, HER3 and HER4. Ligands of this receptor subfamily include epithelial growth factor, TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • the insulin subfamily which includes INS-R, IGF-IR and IR-R, is another subfamily of these receptor tyrosine kinases.
  • the PDGF subfamily includes the PDGF- ⁇ and ⁇ receptor, CSFIR, c- kit and FLK-II.
  • FLK family which consists of the kinase insert domain receptor (KDR), the fetal liver kinase-1 (FLK-1), the fetal liver kinase-4 (FLK-4) and the fms tyrosine kinase-1 (fit-1 ) consists.
  • KDR kinase insert domain receptor
  • FLK-1 the fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • fit-1 fms tyrosine kinase-1
  • the cytosolic tyrosine kinases also consist of a large number of subfamilies, including Src, Frk, Btk, Csk, Abi, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further divided into different receptors.
  • the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk.
  • the Src enzyme subfamily has been linked to oncogenesis.
  • receptor tyrosine kinases and the growth factors that bind them have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. Cell Biol. 129: 895-898, 1995).
  • One of these receptor tyrosine kinases is the fetal liver kiriase " 1, also called FLK-1.
  • the human analogue of FLK-1 is the kinase insert domain-containing receptor KDR, which is also known as vascular endothelial cell growth factor receptor 2 or VEGFR-2 is because it binds VEGF with high affinity.
  • VEGF and KDR represent a ligand-receptor pair , which plays an essential role in the proliferation of vascular endothelial cells and the formation and sprout of blood vessels, which are referred to as vasculogenesis or angiogenesis, which is characterized by an excessive activity of the vascular endothelial growth factor (VEGF) .
  • VEGF actually exists from a family of ligands (Klagsbum and D'Amore, Cytokine &.
  • VEGF vascular endothelial cell growth factor receptor 1
  • Solid tumors can therefore be treated with tyrosine kinase inhibitors, since these tumors rely on angiogenesis for the formation of the blood vessels required to support their growth.
  • These solid tumors include monocyte leukemia, brain,
  • Urogenital, lymphatic, gastric, larynx and lung carcinomas including lung adenocarcinoma and small cell lung carcinoma.
  • Other examples include carcinomas in which overexpression or activation of Raf-activating oncogenes (e.g. K-ras, erb-B) is observed.
  • Raf-activating oncogenes e.g. K-ras, erb-B
  • These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes.
  • VEGF vascular endothelial growth factor
  • VEGF mRNA and protein levels in the eye are increased due to conditions such as retinal venous occlusion in the primate and reduced p0 2 levels in the mouse, which lead to neovascularization.
  • VEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones.
  • the VEGF is also upregulated by the expression of the oncogenes ras, raf, src and p53 mutant (all of which are important in the fight against cancer).
  • Anti-VEGF monoclonal antibodies inhibit the
  • VEGF tumor growth factor
  • VEGF which originates from tumors, does not act as an autocrine mitogenic factor. VEGF therefore contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity.
  • These monoclonal antibodies also inhibit the growth of typically less vascularized human colon carcinomas in thymus-less mice and reduce the number of tumors arising from inoculated cells.
  • Embryo stem cells which usually grow in the form of solid tumors in the nude mouse, do not form any detectable knock-out of both VEGF alleles
  • Ang1 angiopoietin 1
  • Receptor tyrosine kinase TIE-2 it is a new angiogenic factor (Davis et al, Cell, 1996, 87: 1161-1169; Partanen et al,
  • TIE Teyrosine Kinase
  • TIE is used to identify a cell
  • TIE receptor kinases are typically characterized by the presence of an EGF-like domain and an immunoglobulin (IG) -like domain consisting of extracellular folding units that are stabilized by inter-chain disulfide bonds (Partanen et al Curr. Topics Microbiol. Immunol. , 1999, 237: 159-172).
  • IG immunoglobulin
  • Ang1 and its receptor TIE-2 act during the later stages of vascular development, i.e.
  • TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis and thereby the angiogenesis process. Furthermore, inhibition at the kinase domain binding site of VEGFR-2 would block the phosphorylation of tyrosine residues and serve to interrupt the initiation of angiogenesis. It can therefore be assumed that inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or completely eliminate tumor growth. Accordingly, one could treat cancer and others provide diseases associated with inappropriate angiogenesis.
  • the present invention is directed to methods for regulation
  • TIE-2 Modulation or inhibition of TIE-2 for prevention and / or
  • the compounds of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and / or can be used to restore the efficacy of certain existing cancer chemotherapies and radiation treatments.
  • the present invention further relates to the compounds as inhibitors of Raf kinases.
  • Protein phosphorylation is a fundamental process for the regulation of cell functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and consequently the activity of specific target proteins.
  • One of the predominant roles of protein phosphorylation is in signal transduction when extracellular signals are amplified and by a cascade of protein phosphorylation and dephosphorylation events, e.g. B. are propagated in the p21 ras / raf way.
  • the p21 gene was discovered as an oncogene of the Harvey and Kirsten rat sarcoma viruses (H-Ras and K-Ras, respectively).
  • H-Ras and K-Ras characteristic mutations in the cellular Ras gene (c-Ras) have been associated with many different types of cancer.
  • c-Ras characteristic mutations in the cellular Ras gene
  • These mutant alleles that make Ras constitutively active have been shown to transform cells, such as the murine cell line NIH 3T3, in culture.
  • the p21 ras oncogene is an important contributing factor in the development and progression of solid human carcinomas and is mutated in 30% of all human carcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9).
  • the Ras protein is a key element of the signal transduction cascade, which is controlled by growth factor receptors in almost all tissues (Avruch et al. (1994) Trends Biochem. Sei., 19, 279-83) ,
  • Ras is a guanine nucleotide binding protein, and the cycling between a GTP-linked activated and a GDP-linked quiescent form is strictly controlled by Ras endogenous GTPase activity and other regulatory proteins.
  • the Ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP to GDP.
  • Ras is active in the GTP-bound state.
  • endogenous GTPase activity is weakened, and consequently the protein emits constitutive growth signals to "downstream" effectors, such as the Raf kinase enzyme. This leads to the cancerous growth of the cells that produce them Mutants carry (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53).
  • the Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to be able to and not-
  • Transduce receptor tyrosine kinases initiated growth and differentiation signals.
  • Ras Activated Ras is necessary for the activation of the C-Raf-1 proto-oncogene, but the biochemical steps by which Ras activates the Raf-1 protein (Ser / Thr) kinase have now been well characterized. It has been shown to inhibit the effect of active Ras
  • Raf kinase by antisense oligodeoxynucleotides
  • the inhibition of Raf kinase in vitro and in vivo has been associated with the inhibition of growth in a number of different human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).
  • Raf-serine and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a number of different cell systems (Rapp, UR, et al. (1988) in The Oncogene Handbook; T. Curran, EP Reddy and A. Skalka (Ed.) Elsevier Science Publishers; Netherlands, pp. 213-253; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184; Rapp, UR, et al. (1990 ) Inv Curr. Top. Microbiol. Immunol. Potter and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).
  • Raf-1 is expressed in all organs and in all cell lines that have been examined, and A- and B-Raf are expressed in urogenital and brain tissues, respectively (Storm, SM (1990) Oncogene 5: 345-351).
  • Raf genes are proto-oncogenes: they can initiate the malignant transformation of lines if they are expressed in specifically modified forms. Genetic changes that lead to oncogenic activation produce a constitutively active protein kinase by removal or interference with an N-terminal negative regulator domain of the protein
  • Raf-1 protein serine kinase is a candidate for the "downstream" effector of mitogen signal transduction because Raf oncogenes face growth arrest resulting from blockade of cellular Ras activity due to a cellular mutation (Ras revertant cells) or microinjection of anti-Ras antibodies results (Rapp, UR, et al. (1988) in The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, S. 213-253; Smith, MR, et al. (1986) Nature (London) 320: 540-543).
  • Raf-1 protein serine kinase activity is regulated by mitogens via phosphorylation (Morrison, DK, et al. (1989) Cell 58: 648-657), which also effects the subcellular distribution (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184.
  • PDGF platelet growth factor
  • the transiently activated Raf-1 protein serine kinase translocates into the perinuclear area and the
  • Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promotors in transient transfection assays (Jamal, S, et al. (1990) Science
  • Raf-1 protein phosphorylation may be a result of a kinase cascade that is amplified by autophosphorylation, or may be caused entirely by autophosphorylation that is initiated by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation by diacylglycerol (Nishizuka, Y. (1986) Science 233: 305-312).
  • Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, which ultimately results in a cell response.
  • These signal transduction cascades are highly regulated and often overlap, as can be seen from the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore classified according to their specificity for the location of the phosphoryl. H. of serine / threonine kinases and tyrosine kinases.
  • the compounds according to the invention are inhibitors of the enzyme Raf kinase. Since the enzyme is a "downstream" effector of p21 ras , the inhibitors in pharmaceutical compositions for human or veterinary use are found to be useful when inhibiting the Raf kinase pathway, for example in the treatment of tumors and / or cancer cell mediated by Raf kinase.
  • the compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g., murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore responsive to cascade disruption treatment, ie inhibition of Raf kinase.
  • the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route Cancer, including solid cancers, such as
  • carcinomas e.g. the lungs, pancreas, thyroid, bladder or colon
  • myeloid diseases e.g. myeloid leukemia
  • adenomas e.g. villous colon adenoma
  • pathological angiogenesis e.g. metastatic cell migration.
  • the compounds are also useful in the treatment of complement activation dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res, 24: 191-199) and HIV-1 (Human Immunodeficiency Virus Type 1) induced immune deficiency (Popik et al. (1998) J Virol, 72: 6406-6413).
  • the compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in enzyme-based assays, for example assays as described here. In such enzyme-based assays exhibit and cause the compounds of the invention preferably have an inhibiting effect, which is usually by IC 5 o values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.
  • the compounds of the invention are useful in the prophylaxis and / or treatment of diseases which are dependent on the said signaling pathways through interaction with one or more of the said signaling pathways.
  • the present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein.
  • Preferred objects of the invention are therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the Raf kinase pathway.
  • a preferred subject of the invention is therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of Raf kinase.
  • a more preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of one or more Raf kinases, selected from the group consisting of A-Raf, B-Raf and C-Raf-1.
  • a special one preferred subject matter of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.
  • Another object of the present invention is the use of one or more compounds according to the invention in the treatment and / or prophylaxis of diseases, preferably the diseases described here, which are caused, mediated and / or propagated by Raf kinases and in particular diseases caused by
  • Raf kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1 are caused, mediated and / or propagated.
  • the diseases discussed here are usually divided into two groups, hyperproliferative and non-hyperproliferative diseases. In this
  • Context, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are regarded as non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immune deficiency diseases are usually regarded as non-hyperproliferative diseases.
  • brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia, all types of cancer and acute leukemia are usually considered hyperproliferative diseases.
  • cancerous cell growth and in particular cancerous cell growth mediated by Raf kinase is a disease which is an object of the present invention.
  • the present invention therefore relates to compounds according to the invention as pharmaceuticals and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of the diseases mentioned and the use of inventive Compounds for the manufacture of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said diseases comprising the administration of one or more compounds according to the invention to one
  • the compounds according to the invention have an in vivo antiproliferative effect in a xenograft tumor model.
  • the compounds of the invention are administered to a patient with a hyperproliferative disease, e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • a hyperproliferative disease e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • the present compounds are useful for prophylactic or therapeutic purposes.
  • the term "treating" is used to refer to both the prevention of diseases and the treatment of pre-existing conditions.
  • the prevention of proliferation is accomplished by administering the compounds of the invention prior to the development of the apparent disease, e.g., to prevent tumor growth Prevention of metastatic growth, reduction of restenoses associated with cardiovascular surgery, etc.
  • the compounds are used to treat persistent diseases by stabilizing or improving the clinical symptoms of the patient.
  • the host or patient can belong to any mammalian species, e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to enable the active agents to induce cell death or to inhibit migration, usually between about an hour and a week. Cultured cells from a biopsy sample can be used for in vitro testing. The viable cells remaining after treatment are then counted.
  • a therapeutic dose is sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's viability. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • Phospho-AK Phospho-Antibodies
  • the sufferings of interest include, but are not limited to, the following sufferings.
  • the compounds of the invention are useful in the treatment of a number of different conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells is present in the intimal layer of a vessel, resulting in reduced blood flow to this vessel, e.g. B. in neointimal occlusive lesions.
  • Occlusive graft vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, venous graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement and the like.
  • the compounds according to the invention are also suitable as p38 kinase inhibitors.
  • WO 02/44156 describes benzimidazole derivatives other than TIE-2 and / or VEGFR2 inhibitors.
  • WO 99/32436 discloses substituted phenyl ureas as Raf kinase inhibitors. From WO 02/062763 and WO 02/085857 one knows quinolyl, Isoquinolyl and pyridyl urea derivatives as Raf kinase inhibitors. Heteroaryl ureas as p38 kinase inhibitors are described in WO 02/85859.
  • WO 00/42012 are ⁇ -carboxyaryl-diphenylureas as Raf kinase inhibitors and in WO 00/41698 as p38 kinase
  • aryl and heteroaryl-substituted heterocyclic ureas are disclosed in WO 99/32455 as Raf kinase inhibitors and in WO 99/32110 as p38 kinase inhibitors.
  • Other diphenyl urea derivatives are known from WO 99/32463.
  • Substituted heterocyclic urea derivatives as p38 kinase inhibitors are disclosed in WO 99/32111.
  • the invention relates to urea derivatives selected from the group
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
  • Salts of the compounds according to the invention as well as so-called prodrug compounds are salts of the compounds according to the invention as well as so-called prodrug compounds.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups,
  • the term "effective amount” means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human, e.g. is sought or sought by a researcher or medical professional.
  • terapéuticaally effective amount means an amount which, compared to a corresponding subject who has not received this amount, has the following consequences: improved treatment, healing, prevention or elimination of a disease, a clinical picture, a disease state, one Suffering, a disorder or side effects, or even reducing the progression of an illness, suffering or disorder.
  • terapéuticaally effective amount also includes the amounts that are effective in increasing normal physiological function.
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds according to the invention.
  • the starting compounds are generally known. If they are new, they can be manufactured according to methods known per se.
  • the implementation takes place according to methods which are known to the person skilled in the art.
  • the reaction is first carried out in a suitable solvent, optionally in the presence of an organic base, e.g.
  • Triethylamine or an inorganic base such as e.g. an alkali or
  • Alkaline earth metal carbonate Alkaline earth metal carbonate.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF);
  • Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitrover- bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitrover- bonds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • reaction time is between a few minutes and 14 days, the reaction temperature between about
  • a base of the compounds according to the invention can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, aicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, ethanodisulfonic acid, methanoic acid sulfonic acid, methane sulfonic acid, methane acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.
  • Salts with physiologically unacceptable acids e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.
  • the invention further relates to the use of the compounds and / or their physiologically acceptable salts for the preparation of a Medicament (pharmaceutical preparation), in particular by non-chemical means. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to pharmaceutical compositions containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
  • compositions can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition of the disease treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient.
  • such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
  • compositions can be administered for administration by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • Active ingredient is brought together with the carrier (s) or auxiliary (s).
  • compositions adapted for oral administration can be used as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Tablet or capsule the active ingredient with an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water etc. combine.
  • Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed.
  • a flavor, preservative, dispersant and color may also be present.
  • Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it.
  • Lubricants and lubricants such as highly disperse silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrant or solubilizer such as agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medication after taking the capsule.
  • suitable binding agents, lubricants and disintegrants, and also dyes can also be incorporated into the mixture. Suitable binders include starch,
  • Gelatin natural sugars such as glucose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate , Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others.
  • the disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or compressing it dry, a lubricant and a disintegrant are added and the whole is compressed into tablets.
  • a powder mixture is produced by the compound, which has been comminuted in a suitable manner, with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution-reducing agent, such as, for example, paraffin Absorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • a binder such as, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a solution-reducing agent such as, for example, paraffin Absorption accelerator, such as a quaternary salt and / or
  • the powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials, and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials
  • the powder mixture can be run through a tabletting machine, resulting in irregularly shaped lumps which are broken up into granules.
  • the granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
  • the compounds of the invention can also be used with a free-flowing inert Carrier combined and then pressed directly into tablets without performing the granulation or dry pressing steps.
  • a transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer material and a glossy layer of wax may be present.
  • Dyes can be added to coatings to distinguish between different dosage units.
  • Oral liquids e.g. Solution, syrups and elixirs can be prepared in unit dosage forms so that a given quantity contains a given amount of the compound.
  • Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.
  • Dosage unit formulations for oral administration can optionally be enclosed in microcapsules.
  • the formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues.
  • the compounds can be linked to a class of biodegradable polymers suitable for achieving controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutter acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipatic block copolymers of hydrogels.
  • compositions adapted for transdermal administration can be administered as independent patches for prolonged, close contact with the epidermis of the recipient.
  • the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably used as a topical ointment or cream applied.
  • the active ingredient can be either paraffinic or water-miscible
  • Cream base can be used.
  • the active ingredient can be a
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • compositions adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • Formulations in which the vehicle is a solid contain a coarse powder with a particle size, for example in the range of 20-500 micrometers, which is administered in the manner in which snuff is taken up, i.e. by quick inhalation over the
  • Powder Suitable formulations for administration as a nasal spray or
  • compositions adapted for administration by inhalation include fine particulate dusts or mists which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.
  • Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Formulations include aqueous and non-aqueous sterile solutions for injection containing antioxidants, buffers, bacteriostatics and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners.
  • the formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
  • formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of the present invention depends on a number of factors, including, for example. the age and weight of the animal, the exact condition of the disease that requires treatment, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the treating doctor or veterinarian.
  • an effective amount of a compound according to the invention for the treatment of neoplastic growth, for example colon or breast carcinoma generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and particularly typically in the range of 1 to 10 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, which amount as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be used as a proportion of the effective
  • Amount of the compound of the invention can be determined perse. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
  • the invention further relates to medicaments containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a set consisting of separate packs of (a) an effective amount of a compound according to the invention and / or its pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and (b ) an effective amount of another drug ingredient.
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • suitable containers such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, each containing an effective amount of a compound according to the invention and / or its pharmaceutical 05/019192 - 33 -
  • the present compounds are suitable as pharmaceutical active substances for mammals, in particular for humans, in the treatment of tyrosine kinase-related diseases.
  • diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like).
  • the present invention comprises the use of the compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer.
  • Preferred carcinomas for the treatment come from the group of brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma,
  • Larynx and lung cancer are Larynx and lung cancer.
  • Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • Eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
  • a medicament for the treatment or prevention of inflammatory diseases also falls within the scope of the present invention.
  • inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction and the like.
  • compounds according to the invention as claimed in claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-related disease or a tyrosine kinase-related condition in a mammal, this method being a sick mammal such treatment requires a therapeutically effective amount of a compound of the invention.
  • the therapeutic amount depends on the respective disease and can be determined by the person skilled in the art without any great effort.
  • the present invention also includes the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of retinal vascularization.
  • Methods for treating or preventing eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
  • the use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late types of the hypersensitivity reaction, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets also falls within the scope of the present invention.
  • the term "tyrosine kinase-related diseases or conditions” refers to pathological conditions that result from the activity of one or more
  • Tyrosine kinases are dependent.
  • the tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell activities, including proliferation, adhesion and migration as well as differentiation.
  • Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like) ).
  • the present compounds inhibit tumor angiogenesis and thus influence the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995).
  • the angiogenesis-inhibiting properties of the present compounds according to claim 1 are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization.
  • the compounds according to claim 1 are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and
  • Rickets which is also known as oncogenic osteomalacia (Hasegawa et al, Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al, Nature Medicine, Vol. 5, No. 6, pp. 623-628, June 1999). Since VEGF directly promotes osteoclastic bone resorption through the KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the present compounds are also suitable for treatment and prevention of conditions related to bone resorption, such as osteoporosis and Paget's disease. The compounds can be characterized by the fact that they have cerebral edema,
  • the invention thus relates to the use of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the Signal transduction of kinases plays a role.
  • Kinases are preferably selected from the group of tyrosine kinases and Raf kinases.
  • the tyrosine kinases are preferably TIE-2.
  • the use for the treatment of a disease is particularly preferred, the disease being a solid tumor.
  • the solid tumor is preferably selected from the group consisting of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.
  • the solid tumor is also preferably selected from the group consisting of monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • the invention further relates to the use of the compounds according to the invention for the treatment of a disease in which angiogenesis is involved.
  • the disease is preferably an eye disease.
  • the invention further relates to the use for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
  • the inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reaction.
  • the invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, the bone pathology coming from the group of osteosarcoma, osteoarthritis and rickets.
  • the compounds according to claim 1 are suitable for the preparation of a
  • the use for the treatment of diseases preferably from the group of hyperproliferative and non-hyperproliferative diseases.
  • the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis,
  • the cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma and chronic leukemia, chronic leukemia.
  • the compounds of the invention can also be used in conjunction with other well-known therapeutic agents based on their respective
  • Suitability for the condition being treated can be administered.
  • combinations that contain antiresorptive bisphosphonates, such as alendronate and risedronate, integrin blockers (as defined below), such as ⁇ vß3 antagonists, conjugated estrogens such as Prempro®, Premarin® and Endometrion® used in hormone therapy would be beneficial; contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors.
  • SERMs selective estrogen receptor modulators
  • the present compounds are also suitable for combination with known anti-cancer agents.
  • anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative Agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor,
  • HIV protease inhibitors HIV protease inhibitors, reverse transcriptase inhibitors and others
  • Angiogenesis inhibitors are particularly suitable for joint use with radiotherapy.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done.
  • the estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-Dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl -2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, which, however, is not intended to be a limitation.
  • Androgen receptor modulators refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done.
  • the androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, Nilutamide, Flutamide, Bicalutamide , Liarozole and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done.
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9- cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.
  • Cytotoxics refers to compounds that are primarily affected by direct action on cell function lead to cell death or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase
  • the cytotoxics include, for example, tirapazimin, sertenef, cachectin,
  • Dibromodulcite ranimustine, fotemustine, nedaplatin, oxaliplatin,
  • Temozolomide Temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ', 4'-dideshydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1094476, BMS Vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L -valyl-L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797.
  • paclitaxel vindesine sulfate
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-0-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4, 5-kl] acridin-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H, 12H-benzo [de] pyrano [ 3 ', 4': b, 7] indolizino [1, 2b] quinoline-10, 13 (91-1.15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin , BNP1350, BNPI1100, BN80915, BN80942, e
  • antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, 0DN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flabinarababin, capud ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- 3- dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [
  • antiproliferative agents also contain monoclonal antibodies against growth factors other than those already mentioned under the “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which mediate via recombinant virus Gene transfer can be delivered (see, for example, US Patent No. 6,069,134).
  • VEGF receptor kinase assay The VEGF receptor kinase activity is determined by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY). The phosphorylated pEY product is held on a filter membrane and the incorporation of the radioactively labeled phosphate is quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, BI et al. Oncogene (1991) Vol. 6, pp. 1677-1683.) And Flt-1 (Shibuya, M. et al. Oncogene (1990) Vol. 5 , Pp. 519-524) were cloned as glutathione-S-transferase (GST) gene fusion proteins. This was done by cloning the cytoplasmic domain of the KDR kinase as a read-frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione-S-transferase
  • the soluble recombinant GST-kinase domain fusion proteins were found in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) Use of a baculovirus expression vector (pAcG2T, Pharmingen).
  • Tris pH 7.4 50mM Tris pH 7.4, 0.5M NaCl, 5mM DTT, 1mM EDTA, 0.5% Triton X-
  • Tris pH 7.4 50 mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 10% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.
  • Bovine serum albumin BSA] (Sigma).
  • Millipore #MAFC NOB GF / C 96-well glass fiber plate.
  • the Sf21 cells were with the recombinant virus in an m.o.i.
  • volume lysis buffer lysed and then centrifuged for 1 hour at 100,000xg. The supernatant was then passed through a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer and with 5
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • Cultivated human umbilical vein endothelial cells proliferate in response to treatment with VEGF and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • VEGF vascular endothelial growth factor
  • bFGF Basic fibroblast growth factor
  • Frozen HUVECs as primary culture isolates are obtained from Clonetics Corp. The cells are in the endothelial growth medium (endothelial
  • NUNCLON 96-well polystyrene tissue culture plates (NUNC # 167008).
  • Dulbecco modified Eagle medium with 1 g / ml glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal
  • [Methyl- 3 H] -thymidine (20 Ci / mmol; Dupont-NEN) is diluted to 80 ⁇ Ci / ml with DMEM medium with a low glucose content.
  • Hank's balanced salt solution Mediatech
  • 1 mg / ml bovine serum albumin Boehringer-Mannheim
  • Cell lysis solution 1N NaOH, 2% (w / v) Na 2 CO 3 .
  • HUVEC single cell layers kept in EGM are harvested by trypsin treatment and inoculated in a density of 4000 cells per 100 ⁇ l assay medium per well in 96-well plates. The growth of the cells is stopped for 24 hours at 37 ° C. in a humid atmosphere containing 5% CO 2 . Procedure 2
  • the growth stop medium is replaced by 100 ul assay medium containing either the constituent (0.25% [v / v] DMSO) or the desired final concentration of the test compound. All determinations are carried out in triplicate. The cells are then incubated for 2 hours at 37 ° C / 5% CO 2 so that the test compounds can penetrate the cells. Procedure 3
  • the medium is suctioned off and the cells are washed twice with washing medium (400 ⁇ l / well, then 200 ⁇ l / well).
  • the washed, adherent cells are then solubilized by adding cell lysis solution (100 ⁇ l / well) and heating to 37 ° C. for 30 minutes.
  • the cell lysates are transferred to 7 ml glass scintillation tubes containing 150 ul water.
  • the scintillation cocktail (5 ml / tube) is added and the radioactivity associated with the cells is determined by liquid scintillation spectroscopy. According to these assays, the compounds of the formula I VEGF-
  • Inhibitors are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, e.g. diabetic retinopathy, and for the treatment of carcinomas, e.g. solid tumors.
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of
  • Tyrosine kinases e.g. FGFR1 and Src family; for the relationship between Src kinases and VEGFR kinases see Eliceiri et al, Molecular Cell, Vol.
  • the T7E-2 tests can e.g. can be carried out analogously to the methods specified in WO 02/44156.
  • the assay determines the inhibitory activity of the substances to be tested in the phosphorylation of the substrate poly (Glu, Tyr) by Tie-2-kinase in the presence of radioactive 33 P-ATP.
  • the phosphorylated substrate poly Glu, Tyr
  • Substrate binds to the surface of one during the incubation period
  • customary work-up means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporated and purified by chromatography
  • the mixture is mixed with water and extracted with ethyl acetate.
  • the collected organic phases are dried with anhydrous sodium sulfate, filtered and evaporated.
  • the residue is triturated with diethyl ether. 2.8 g of 5- (4-nitrophenoxy) benzo [1,2,5] thiadiazole are obtained; Rf (CH2Cl2) 0.65; EI-MS (M + H) + 274.
  • the nitro compound is hydrogenated with Raney nickel to the desired compound.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient according to the invention is melted with 100 g soy lecithin and 1400 g cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of
  • Benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • Example E tablets
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of an active ingredient according to the invention in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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Abstract

L'invention concerne de nouveaux dérivés d'urée qui sont des inhibiteurs des tyrosine kinases, notamment du récepteur TIE-2, et des raf kinases et qui peuvent être utilisés pour le traitement de tumeurs.
EP04763077A 2003-07-30 2004-07-02 Derives d'uree et leur utilisation comme inhibiteurs des tyrosine kinases Withdrawn EP1651626A1 (fr)

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DE10334663A DE10334663A1 (de) 2003-07-30 2003-07-30 Harnstoffderivate
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ME00275B (fr) 1999-01-13 2011-02-10 Bayer Corp DIPHENYLUREES A SUBSTITUANTS ω-CARBOXYARYLES, INHIBITRICES DE KINASE RAF
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EP1158985B1 (fr) 1999-01-13 2011-12-28 Bayer HealthCare LLC DIPHENYLE UREES A SUBSTITUTION OMEGA-CARBOXY ARYLE EN TANT QU'INHIBITEURS DE LA KINASE p38
WO2003068229A1 (fr) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation N-oxydes de pyridine, de quinoline, et d'isoquinoline en tant qu'inhibiteurs de kinase
SI1478358T1 (sl) 2002-02-11 2013-09-30 Bayer Healthcare Llc Sorafenib tozilat za zdravljenje bolezni, značilnih po abnormalni angiogenezi
US7557129B2 (en) 2003-02-28 2009-07-07 Bayer Healthcare Llc Cyanopyridine derivatives useful in the treatment of cancer and other disorders
EP1636585B2 (fr) 2003-05-20 2012-06-13 Bayer HealthCare LLC Diaryl-urees presentant une activite d'inhibition des kinases
EP1663978B1 (fr) 2003-07-23 2007-11-28 Bayer Pharmaceuticals Corporation Omega-carboxyaryldiphenyluree fluoro-subtituee pour le traitement et la prevention de maladies et d'etats pathologiques
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